Neural tube defects (NTD) are congenital malformations arising from incomplete neural tube closure during early embryogenesis. Most NTD in humans show complex inheritance patterns, with both genetic and environmental factors involved in the etiology of this malformation. More than 120 mouse models for human NTD exist. NTD have been observed in mice deficient for the Zic family genes, Zic1, Zic2, and Zic3. We performed mutation analysis in the human orthologs of these genes using DNA material from a large panel of NTD patients. In ZIC2 we identified a deletion of one codon that encodes an alanine residue located in the amino terminal alanine stretch of the protein. The deletion was present in one patient, but not in 364 controls. That may suggest a role-albeit small-of this variant in the etiology of NTD in humans. Transmission disequilibrium testing of a frequent polymorphism in the ZIC2 gene (1059C > T, H353H) in parent-spina bifida aperta child triads showed no association with NTD. One silent polymorphism (858G > A, V286V) of unknown significance was identified in ZIC3. Neither mutations nor polymorphisms were found in the coding region or flanking sequences of ZIC1. Our data indicate that ZIC1, ZIC2, and ZIC3 are not major risk factors for NTD in humans.

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